Ibuprofen p-hydroxyphenylurea ester

ABSTRACT

Ibuprofen p-hydroxyphenylurea ester having the formula II:  II &lt;IMAGE&gt;   was prepared from the free acid, ibuprofen [+/-2-(p-isobutylphenyl)propionic acid](I).

BACKGROUND OF THE INVENTION

Ibuprofen (Motrin®) is one of the more recent commonly prescribed,non-steroidal drugs used in the treatment of arthritis. It is used indosages of 300-400 mg. tablets up to 8 per day. The taste of thispropionic acid derivative is extremely repulsive, which makes itnecessary to coat the tablet or to capsulate the product. It is verydifficult to veil this taste by other added flavors in syrupformulations. Therefore, the practical, effective dosage are coatedtablets or capsules which in view of the dosage requirement are of largesize and thus present a difficulty of swallowing, particularly forchildren or older people.

It has now been found that the novel p-hydroxyphenylurea ester ofibuprofen II provides an effective form of the active parent compound,Compound II, is nearly tasteless and thus permits the production ofliquid forms for administration specifically suitable for the pediatricor geriatric patient.

The ethyl ester of ibuprofen is named in U.S. Pat. No. 3,228,831. Thisester is an oil and its taste qualities are not markedly different fromthe parent ibuprofen.

FIELD OF THE INVENTION

This invention is directed to nearly tasteless ibuprofenp-hydroxyphenylurea ester and the process of production thereof.

The novel compound and the process of production thereof can beillustratively represented as follows: ##STR2##

The invention includes besides the novel compound II, the process tomake compound II.

The compound I, ibuprofen, can be alternatively namedp-(iso-butyl)hydratropic [see hydratropic acid, Dictionary of OrganicCompounds, Heilbron, Vol. II, p. 699, New York, Oxford Press, 1953]orα-methyl-α-(p-isobutylphenyl)acetic acid. Consequently the compoundherein preferably named as ibuprofen p-hydroxyphenyl ester can be namedby any of the alternative names for ibuprofen.

The process of this invention comprises: treating ibuprofen I dissolvedin an inert organic solvent with a trialkylamine in which the alkylgroup is of 1 to 4 carbon atoms, inclusive, between -50° to 0° C.;treating the mixture with isobutylchloroformate and subsequently with(p-hydroxyphenyl)urea dissolved in an inert organic base at atemperature of -10° to 40° C.

PREFERRED EMBODIMENT OF THE INVENTION

The new ester II, ibuprofen p-hydroxyphenylurea ester, was tested in thehind paw test for anti-inflammatory efficacy. It was found that theproduct had a potency of 1.7 × aspirin which is approximately the sameas ibuprofen itself. On the other hand in a taste panel, where 9 is thehighest score (excellent taste) and zero is the lowest, ibuprofen (I)has a score of 3, while the p-hydroxyphenylurea ester has a score of 7.

The ester II can thus be administered orally in the form of pills,tablets, dragees, and the like containing specific dosages, 100-500 mg.,of the active material. Similarly, the ester II may be administered inliquid forms such as solutions, suspensions, syrups, emulsions, withflavors and common solvents or diluents, containing precise dosages perliquid unit dosage such as from 75 to 500 mg. per teaspoon (5 ml.) orper tablespoon (15 ml.).

In carrying out the process of this invention, the starting compoundibuprofen (I) is dissolved in an inert organic solvent, e.g. ether, suchas diethyl ether, dipropylether, dioxane, tetrahydrofuran, ketones suchas acetone, diethyl ketone, pentanones, hexanone, cyclohexanone or thelike and the solution is first admixed with a trialkyl amine e.g.triethyl-, tripropyl-, methyldiethylamine or the like at temperaturesbetween -50° to 0° C., conveniently at room temperature. To thisreaction after cooling to between -30° to 0° C. isobutylchloroformate isadded, and shortly thereafter the p-hydroxyphenylurea at a temperatureof -10° to 40° C. The mixture is allowed to react between 10 to 120minutes, longer times can be used, however, no advantages are obtainedthereby. In the preferred embodiment of this invention the threereagents used, that is a trialkylamine, isobutyl chloroformate andp-hydroxyphenylurea are used in a ratio of 1 to 1.5 mole eqivalent to 1mole equivalent of ibuprofen. Larger ratios are operative, but are notadvantageous.

After the reaction is terminated the reaction mixture is acidified to apH of 1.5-3.0 and the product II is recovered by extraction with aninert organic solvent in conventional manner.

EXAMPLE 1 Ibuprofen p-hydroxyphenylurea ester

Ibuprofen, p-isobutylhydratropic acid, (8 g., 3.8 × 10⁻² mole) wasdissolved in 10 ml. of anhydrous acetone. To this solution was added3.92 g. (3.8 × 10⁻² mole) of triethylamine. This was cooled to -20° C.under nitrogen and thereto was added 5.30 g. (3.8 × 10⁻² mole) ofisobutyl chloroformate. The resulting solution was allowed to warm tobetween -5° C. to 0° C. and thereupon 5.90 g. (3.8 × 10⁻² mole) ofp-hydroxyphenylurea in 50 ml. of pyridine was added under continuousstirring. After 1 hour the pH was adjusted to 2 by adding a sufficientamount of aqueous dilute 1.0N hydrochloric acid. The acidified solutionwas then extracted with ether, the ether layer dried over anhydrousmagnesium sulfate and the solvent removed in vacuo. The resultingcrystals were recrystallized from methanol-water providing ≅3 g. ofibuprofen p-hydroxyphenylurea ester of melting point 155°-159° C.

Anal. calcd. for C₂₀ H₂₄ N₂ O₃ : C, 70.56; H, 7.11; N, 8.23. Found: C,70.25; H, 7.17; N, 8.11.

EXAMPLE 2 Pediatric Suspension

A pediatric suspension containing 82 mg. of the ester which isequivalent to 50 mg. of ibuprofen per teaspoon (5 ml.) is made from thefollowing types and amounts of ingredients

    ______________________________________                                        Ibuprofen p-hydroxyphenylurea ester                                                                    16.4     gm.                                         Tragacanth               10.0     gm.                                         Benzoic acid             2.0      gm.                                         Sodium saccharin         1.0      gm.                                         Glycerin                 10.0     ml.                                         Peppermint oil           0.75     ml.                                         Purified water, q.s.     1000     ml.                                         ______________________________________                                    

The ibuprofen p-hydroxyphenylurea is mixed with 500 ml. of the water.The tragacanth, saccharin and glycerin are triturated and added to thewater. The benzoic acid and peppermint oil are added to the mixture in asmall amount of water. Purified water is added to volume. One teaspoonof this suspension is administered to children 1-4 times a day.

EXAMPLE 3 Suspension

    ______________________________________                                        Ibuprofen p-hydroxyphenylurea ester                                                                    131.2    gm.                                         Microcrystalline cellulose                                                                             12.0     gm.                                         Sodium carboxymethylcellulose                                                                          10.0     gm.                                         Cherry flavor            0.5      gm.                                         Purified water, q.s.     1000     ml.                                         ______________________________________                                    

Each teaspoonful (5 ml.) contains 656 mg. of the ester which isequivalent to 400 mg. of ibuprofen. The microcrystalline cellulose isdispensed in the water with a high-shear mixer. The sodiumcarboxymethylcellulose is added and dissolved by means of a high-shearmixer. The ester and flavor are added and mixed and the wholehomogenized. This is administered to adults at a dose of one teaspoonful1-4 times a day.

I claim:
 1. Ibuprofen p-hydroxyphenyurea ester having the formula II:##STR3##